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T-Regulatory Cell and CD3 Depleted Double Umbilical Cord Blood Transplantation in Hematologic Malignancies

This study has been withdrawn prior to enrollment.
(Replaced by a new study)
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01163201
First received: May 26, 2010
Last updated: March 4, 2014
Last verified: March 2014
  Purpose

This is a unique dose-escalation trial that will titrate doses of umbilical cord blood (UCB) Treg and CD3+ Teff cells with the goal of infusing as many CD3+ Teff cells as possible without conferring grade II-IV acute graft-versus-host disease (GVHD).

In this study, the investigators propose to add UCB Treg and UCB CD3+ Teff cells to the two TCD UCB donor units with the goal of transplanting as many CD3+ Teff cells as possible without reintroducing risk of acute GVHD. The investigators hypothesize that Treg will permit the reintroduction of CD3+ Teff cells that will provide a bridge while awaiting HSC T cell recovery long term. The co-infusion of Treg will prevent GVHD without the need for prolonged pharmacologic immunosuppression.


Condition Intervention Phase
Hematologic Malignancy
Acute Myeloid Leukemia
Acute Lymphocytic Leukemia
Chronic Myelogenous Leukemia in Blast Crisis
Anemia, Refractory, With Excess of Blasts
Chronic Myeloproliferative Disease
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Marginal Zone B-cell Lymphoma
Follicular Lymphoma
Lymphoplasmacytic Lymphoma
Mantle-Cell Lymphoma
Prolymphocytic Lymphoma
Large Cell Non-Hodgkin's Lymphoma
Lymphoblastic Lymphoma
Burkitt's Lymphoma
High Grade Non-Hodgkin's Lymphoma
Biological: Treg cells
Biological: CD3+ Teff cells
Drug: Fludarabine
Drug: Cyclophosphamide
Radiation: Total body irradiation
Biological: Umbilical cord blood transplantation
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Optimization of the T Regulatory Cell and T Effector Cell Doses in Recipients of Double UCB Transplantation for Treatment of Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Optimal Cell Dose Mixture [ Time Frame: Day 0 ] [ Designated as safety issue: Yes ]
    Determine the optimal cell dose mixture of UCB T regulatory and CD3+ T effector cells without the development of grade II-IV acute GVHD


Secondary Outcome Measures:
  • Determine incidence of infusional toxicity [ Time Frame: 48 hours ] [ Designated as safety issue: Yes ]
    reaction that occurs with 48 hours of product infusion

  • Incidence of neutrophil recovery [ Time Frame: Day 42 ] [ Designated as safety issue: Yes ]
    Determine the incidence of neutrophil recovery (absolute neutrophil count ≥ 500/uL) at day 42

  • Incidence of double and single chimerism [ Time Frame: Day +21, Day +180, 1 Year ] [ Designated as safety issue: No ]
    Determine incidence of double and single unit chimerism at various time points

  • Incidence of Viral and Fungal Infections [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
    Determine incidence of viral and fungal infections at 1 year

  • 1 Year Survival [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    Estimate the probability of survival at 1 year

  • Incidence of Grade III-IV Acute Graft-Versus-Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Determine the incidence of grade III-IV acute GVHD at day 100

  • Incidence of Treatment Related Death [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
    Determine the incidence of treatment related mortality (TRM) at 6 months

  • Incidence of Platelet Recovery [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    Determine the incidence of platelet recovery (platelet count ≥ 50,000/uL) at 1 year

  • Incidence of Chronic Graft-Versus-Host Disease [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    Determine the incidence of chronic GVHD at 1 year

  • Incidence of Relapse [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
    Determine the incidence of relapse at 1 year


Enrollment: 0
Study Start Date: January 2014
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treg Plus CD3+Teff Treatment
Includes dose adjustment of T regulatory (Treg) and CD3+ T effector (CD3+ Teff) cells in recipients of double UCB transplantation
Biological: Treg cells
Given by infusion on Day 0 after transplantation - Five doses of Treg (3 x 10^6/kg, 10 x 10^6/kg, 30 x 10^6/kg, 100 x 10^6/kg and 300 x 10^6/kg)
Biological: CD3+ Teff cells
Given by infusion on Day 0 after transplantation - 5 doses of CD3+ Teff cells (3 x 10^6 cells/kg, 6 x 10^6 cells/kg, 9 x 10^6 cells/kg, 12 x 10^6 cells/kg, and 15 x 10^6 cells/kg with the latter dose representing the median number of CD3+ cells in two UCB unit grafts
Drug: Fludarabine
Given intravenously on Days -8 through -6, 25 mg/m^2 over 1 hour
Other Name: Fludara
Drug: Cyclophosphamide
Given intravenously on Day -7 and -6, 60 mg/kg
Other Name: Cytoxan
Radiation: Total body irradiation
Given on Days -4 through -2, 165 cGY twice a day.
Biological: Umbilical cord blood transplantation
Infusion given on day 0
Other Name: UCBT

Detailed Description:

Based on prior studies, the first patient will start at lowest dose combination (3 x 10^6/kg of Treg and 3 x 10^6/kg of CD3+ Teff cells).

One patient will be entered at each level with a minimum of 35 days to observe the patient prior to moving to the next dose level. (1) If GVHD does not occur, a "successful step", then the CD3+ Teff cell dose will increase to the next higher level for the next patient; (2) If GVHD occurs, a "failed step", then Treg dose will increase to the next higher level for the next patient. It would take a minimum of 5 (if no GVHD) and maximum of 9 patients (if GVHD is observed at each level) to complete all Treg:CD3+ Teff cell combinations.

An additional 10 patients will be enrolled to verify that this reflects the optimal combination and evaluate its safety profile.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Only patients requiring a double umbilical cord blood (UCB) transplant are to be considered for this study.

UCB Requirements

  • Three UCB units are required - one for Treg production and two for UCB transplant. The unrelated UCB donors must be 4-6/6 HLA-A, B, DRB1 matched with the recipient (HLA matching using molecular techniques: A and B to antigen level resolution and DR to allele level resolution). Suitable UCB units will be selected according to the University Of Minnesota UCB Graft Selection Algorithm.
  • Suitable UCB units must be ABO matched.

Disease Criteria:

  • Patients aged 18 to 55 years
  • Acute Myeloid Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy (if patient refuses or is disqualified from alternative protocols), or in 3rd or higher complete remission (CR).
  • Acute Lymphocytic Leukemia: with morphologically persistent disease in a representative bone marrow aspirate sample with ≤ 10% blasts after at least 1 cycles of chemotherapy, or in 3rd or higher CR
  • Chronic Myelogenous Leukemia in Blast Crisis: with ≤10% residual blasts in the bone marrow aspirate after at least 1 cycle of induction chemotherapy in combination with a tyrosine kinase inhibitor (TKI)
  • Refractory Anemia with Excess Blasts: (≤ 10%) in representative bone marrow aspirate sample of blasts after 1 cycle of induction chemotherapy. If treated with hypomethylating agents, patients are eligible if blast count is ≤ 10% after 4 cycles or evidence of stable or progressive disease after at least 2 cycles.
  • Chronic Myeloproliferative Disease
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Marginal Zone B-Cell Lymphoma or Follicular Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
  • Lymphoplasmacytic Lymphoma, Mantle-Cell Lymphoma, Prolymphocytic Leukemia: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
  • Large Cell Non-Hodgkin's Lymphoma: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
  • Lymphoblastic Lymphoma, Burkitt's Lymphoma, and other High-Grade NHL: disease must be refractory after at least two chemotherapy regimens or is chemotherapy sensitive but has residual nodal disease of ≥ 5 cm
  • Performance Status, Age, and Organ Function
  • Adequate performance status defined as a Karnofsky score ≥ 80%
  • Adequate organ function defined as:

    • Renal: creatinine < 2.0 mg/dL,
    • Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal,
    • Pulmonary function: DLCOcorr > 50% normal,
    • Cardiac: left ventricular ejection fraction > 45%
  • Voluntary written informed consent signed before performance of any study-related procedure not part of normal medical care

Exclusion Criteria:

  • Available medically suitable HLA-identical related donor
  • Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days)
  • History of HIV infection
  • Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy
  • Prior myeloablative transplant within the last 6 months
  • Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation
  • Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tositumomab (Bexxar) as part of their salvage therapy (not eligible for myeloablative umbilical cord blood transplant)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01163201

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States, 55445
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Claudio Brunstein, MD, PhD Masonic Cancer Center, University of Minnesota
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01163201     History of Changes
Other Study ID Numbers: 2009LS018, MT2009-03, 0910M73595
Study First Received: May 26, 2010
Last Updated: March 4, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Blast Crisis
Burkitt Lymphoma
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Follicular
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Myeloproliferative Disorders
Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Waldenstrom Macroglobulinemia
Anemia
Blood Protein Disorders
Bone Marrow Diseases
Carcinogenesis
Cardiovascular Diseases
Cell Transformation, Neoplastic
DNA Virus Infections
Epstein-Barr Virus Infections
Hematologic Diseases
Hemorrhagic Disorders

ClinicalTrials.gov processed this record on November 27, 2014